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Research ArticleArticle

SR 144528, an Antagonist for the Peripheral Cannabinoid Receptor that Behaves as an Inverse Agonist

Marielle Portier, Murielle Rinaldi-Carmona, Florence Pecceu, Thérèse Combes, Caroline Poinot-Chazel, Bernard Calandra, Francis Barth, Gérard Le Fur and Pierre Casellas
Journal of Pharmacology and Experimental Therapeutics February 1999, 288 (2) 582-589;
Marielle Portier
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Murielle Rinaldi-Carmona
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Florence Pecceu
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Thérèse Combes
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Caroline Poinot-Chazel
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Bernard Calandra
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Francis Barth
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Gérard Le Fur
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Pierre Casellas
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Abstract

In the present report, we investigated in detail the effects of SR 144528, a selective antagonist of the peripheral cannabinoid receptor (CB2), on two well-characterized functions mediated by CB2: the induction of the early response gene krox24 and the inhibition of adenylyl cyclase. We generated Chinese hamster ovary cells doubly transfected with human CB2 and a luciferase reporter gene linked to either the murine krox24 regulatory sequence or multiple cAMP responsive elements. Our results show that (1) SR 144528 antagonizes the effect of receptor agonists—it inhibits the krox24 reporter activity and prevents the inhibition of forskolin-induced cAMP reporter activity mediated by CP 55,940; (2) CB2 is autoactivated—CB2 mediates signaling in the absence of ligand, and this basal activity is reduced by pretreating the cells with pertussis toxin; (3) SR 144528 is an inverse agonist—it reproduces the effects of pertussis toxin; and (4) inhibition of precoupled CB2 by a long-term pretreatment of cells with SR 144528 potentiates krox24 response to cannabinoid receptor agonists and restores activation of adenylyl cyclase. Taken together, these data provide evidences for the inverse agonist property of SR 144528 and the constitutive activation of CB2 in Chinese hamster ovary-expressing cells.

Footnotes

  • Send reprint requests to: Marielle Portier, Immunopharmacology Department of Sanofi Recherche, 371 rue du Pr. J. Blayac, 34184 Montpellier cedex 04, France. E-mail:marielle.portier{at}tls1.elfsanofi.fr.

  • Abbreviations:
    GPCR
    G protein-coupled receptor
    CB1
    central cannabinoid receptor
    CB2
    peripheral cannabinoid receptor
    CHO
    Chinese hamster ovary
    CKL
    CHO cells expressing krox24-luciferase
    CKL-CB2
    CKL cells expressing CB2, CRE, cAMP responsive element
    CCL
    CHO cells expressing CRE-luciferase, CCL-CB2, CCL cells expressing CB2
    RLU
    relative light unit
    RLU
    relative light unit
    PMA
    phorbol-12-myristate-13-acetate
    AC
    adenylyl cyclase
    MAPK
    mitogen-activated protein kinase
    PTX
    pertussis toxin
    Δ9-THC
    Δ9-tetrahydrocannabinol
    FSK
    forskolin
    • Received March 18, 1998.
    • Accepted August 10, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 288 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 288, Issue 2
1 Feb 1999
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Research ArticleArticle

SR 144528, an Antagonist for the Peripheral Cannabinoid Receptor that Behaves as an Inverse Agonist

Marielle Portier, Murielle Rinaldi-Carmona, Florence Pecceu, Thérèse Combes, Caroline Poinot-Chazel, Bernard Calandra, Francis Barth, Gérard Le Fur and Pierre Casellas
Journal of Pharmacology and Experimental Therapeutics February 1, 1999, 288 (2) 582-589;

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Research ArticleArticle

SR 144528, an Antagonist for the Peripheral Cannabinoid Receptor that Behaves as an Inverse Agonist

Marielle Portier, Murielle Rinaldi-Carmona, Florence Pecceu, Thérèse Combes, Caroline Poinot-Chazel, Bernard Calandra, Francis Barth, Gérard Le Fur and Pierre Casellas
Journal of Pharmacology and Experimental Therapeutics February 1, 1999, 288 (2) 582-589;
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